The pharmaceutical industry is in search of a treatment and/or prophylaxis of proliferative diseases, disorders, or conditions such as cancers and cancer metastasis. These diseases, disorders, or conditions affect a large portion of the population, leading to suffering and possibly death.
Cancer is infrequently a localized disease as cancer cells detach from the primary tumor, translocate to distant sites, and grow as secondary colonies at the new anatomic locations leading to metastatic cancer. The motility of cancer cells is associated with cancer metastasis. The establishment of secondary colonies also is associated with the development of new blood vessels which supply the newly formed colony with blood and nutrients.
Development and progression of these diseases or disorders involve some form of intracellular signal transduction. Signal transduction is critical to normal cellular homeostasis and is the process of relaying extracellular messages, e.g., chemical messages in the form of growth factors, hormones and neurotransmitters, via receptors, e.g., cell-surface receptors, to the interior of the cell. Protein-tyrosine kinase enzymes play a central role in this biological function.
The above enzymes catalyze the phosphorylation of specific tyrosine residues to form tyrosine phosphorylated residues. The tyrosine-phosphorylated proteins are involved in a range of metabolic processes, from proliferation and growth to differentiation. An example of this class of enzymes is the receptor of the hepatocyte growth factor (HGF) (also known as the scatter factor (SF)), known as c-Met. HGF is a pleiotropic growth factor that, besides promoting cell survival and proliferation, has the ability to dissociate epithelial sheets and to stimulate cell motility. The dissociation of cell sheets and stimulation of cell motility is associated with the formation of new blood vessels, known as angiogenesis.
HGF stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of cellular targets including epithelial and endothelial cells, hematopoietic cells, neurons, melanocytes, as well as hepatocytes. These pleiotropic effects play important roles during development and tissue regeneration. HGF signaling is also implicated in several human cancers including colon, breast, lung, thyroid, and renal carcinomas, several sarcomas, and glioblastoma. The ability of HGF to initiate a program of cell dissociation and increased cell motility coupled with increased protease production promotes aggressive cellular invasion and is linked to tumor metastasis.
Cell dissociation and increased cell motility, such as that induced by HGF, is also associated with angiogenesis. Angiogenesis is a complex and multi-step process that is essential for normal vascularization and wound repair. However, when the angiogenic process is not tightly regulated, persistent and uncontrolled neovascularization occurs, which contributes to tumor neovascularization and cancer metastasis.
HGF signals through its cell-surface receptor. Upon HGF binding, several tyrosine residues within the c-Met intracellular domain are phosphorylated, some of which mediate the binding of signaling proteins such as Grb2. Grb2 binding is involved in HGF-stimulated tubulogenesis, and is thought to link c-Met with small GTP-binding proteins such as Rho and Rac, which are required for HGF-stimulated cytoskeletal rearrangements and cell motility. Further, VEGF and bFGF are among the most potent regulators of angiogenesis, and share intracellular signaling mediators with a variety of angiogenesis signaling pathways. Folkman J., EXS. 79:1-8 (1997).
The foregoing indicates that there is a need for a method of inhibiting cell motility and angiogenesis. There further exists a need for inhibiting cell motility and angiogenesis induced by HGF. There further exists a need for inhibiting HGF, VEGF and bFGF-stimulated cell migration, cell proliferation, and/or formation of capillary-like structure. There further exists a need for a method of treating or preventing diseases such as cancers and cancer metastasis in mammals.
These advantages of the present invention will be apparent from the detailed description of the embodiments of the invention set forth below.